Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay

Poli, Antoine; Moulouel, Boualem; Mirmiran, Arienne; Puy, Hervé; Lefèbvre, Thibaud; Gouya, Laurent

doi:10.3390/metabo11120798

Cited by 17 publications

(12 citation statements)

References 66 publications

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“…This could explain the protective role of iron deficiency in EPP despite its dual opposite effect in the heme synthesis regulation. Indeed, the iron cannot be used by abnormal FECH to form heme in these patients, but it became beneficial in preventing further PPIX accumulation ( Poli et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Finally, the iron depletion in EPP does not appear to be related to chronic inflammation ( Barman-Aksoezen et al, 2017 ). Although the mechanisms explaining how iron is kept low in EPP remain to be identified, there is accumulating evidence that iron deficiency can mitigate disease expression of EPP ( Poli et al, 2021 ). In the bone marrow, heme synthesis is mainly controlled by the intracellular labile iron pool by post-transcriptional regulation.…”

Section: Introductionmentioning

confidence: 99%

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Microcytosis in Erythropoietic Protoporphyria

et al. 2022

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Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans. This disorder is characterized by painful skin photosensitivity, due to excessive protoporphyrin IX (PPIX) production in erythrocytes. Although several papers report the presence of iron deficiency anemia in about 50% of EPP patients, there is still no a conclusive explanation of the why this occurs. In the present work, we explored hematological indices and iron status in 20 unrelated Italian EPP patients in order to propose a new hypothesis. Our data show that microcytosis is present in EPP patients also in the absence of anemia and iron deficiency with a link between PPIX accumulation and reduced MCV, probably indicating an indirect condition of heme deficiency. Patients studied had a downward shift of iron parameters due to increased hepcidin concentrations only in a state of repleted iron stores. Interestingly, hemoglobin synthesis was not limited by iron supply except in cases with further iron loss, in which concomitantly increased soluble transferrin (Tf) receptor (sTfR) levels were detected. The mechanisms involved in the iron uptake downregulation in EPP remain unclear, and the role of PPIX accumulation in microcytosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microcytosis in Erythropoietic Protoporphyria

et al. 2022

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“…Hence, cells have specific regulatory mechanisms that couple heme synthesis with utilization. This is observed in the diversity of phenotypes caused by disorders of heme synthesis, or in loss of function in model organisms ( Balwani and Desnick, 2012 ; Chen et al, 2019 ; Peoc’h et al, 2019 ; Poli et al, 2021 ; Chung et al, 2014 ; Hildick-Smith et al, 2013 ; Phillips et al, 2019 ; Wang et al, 2011 ; Yien et al, 2017 ; Troadec et al, 2011 ; Ducamp et al, 2021 ). Although defects in heme synthesis are often associated with hematologic diseases, loss of function studies and disease phenotypes make clear that many tissues and pathways depend on the correct regulation of heme synthesis for their function.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

Yien

Perfetto

2022

Front. Cell Dev. Biol.

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Heme plays a central role in diverse, life-essential processes that range from ubiquitous, housekeeping pathways such as respiration, to highly cell-specific ones such as oxygen transport by hemoglobin. The regulation of heme synthesis and its utilization is highly regulated and cell-specific. In this review, we have attempted to describe how the heme synthesis machinery is regulated by mitochondrial homeostasis as a means of coupling heme synthesis to its utilization and to the metabolic requirements of the cell. We have focused on discussing the regulation of mitochondrial heme synthesis enzymes by housekeeping proteins, transport of heme intermediates, and regulation of heme synthesis by macromolecular complex formation and mitochondrial metabolism. Recently discovered mechanisms are discussed in the context of the model organisms in which they were identified, while more established work is discussed in light of technological advancements.

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“…The requirement of SCoA as a substrate integrates heme biosynthesis with oxidative respiration, and as a result the two pathways are synchronized under normal healthy conditions. ALAS activity is additionally synchronized with cellular iron transport as porphyrin biosynthesis and iron transport unite in the final step of heme production wherein the enzyme ferrochelatase inserts ferrous iron into protoporphyrin IX to yield heme ( Kafina and Paw, 2017 ; Poli et al, 2021 ). As a result of the central position of ALAS in these fundamental biochemical pathways ALAS activity is highly regulated and new modes of ALAS regulation continue to be discovered ( Tanimura et al, 2016 ; Zhang et al, 2017 ; Liu et al, 2018 ; Peoc'h et al, 2019 ; Bailey et al, 2020 ; Nomura et al, 2021 ; Rondelli et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms

Hunter

Ferreira

2022

Front. Mol. Biosci.

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5-Aminolevulinate synthase (ALAS; E.C. 2.3.1.37) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the key regulatory step of porphyrin biosynthesis in metazoa, fungi, and α-proteobacteria. ALAS is evolutionarily related to transaminases and is therefore classified as a fold type I PLP-dependent enzyme. As an enzyme controlling the key committed and rate-determining step of a crucial biochemical pathway ALAS is ideally positioned to be subject to allosteric feedback inhibition. Extensive kinetic and mutational studies demonstrated that the overall enzyme reaction is limited by subtle conformational changes of a hairpin loop gating the active site. These findings, coupled with structural information, facilitated early prediction of allosteric regulation of activity via an extended C-terminal tail unique to eukaryotic forms of the enzyme. This prediction was subsequently supported by the discoveries that mutations in the extended C-terminus of the erythroid ALAS isoform (ALAS2) cause a metabolic disorder known as X-linked protoporphyria not by diminishing activity, but by enhancing it. Furthermore, kinetic, structural, and molecular modeling studies demonstrated that the extended C-terminal tail controls the catalytic rate by modulating conformational flexibility of the active site loop. However, the precise identity of any such molecule remains to be defined. Here we discuss the most plausible allosteric regulators of ALAS activity based on divergences in AlphaFold-predicted ALAS structures and suggest how the mystery of the mechanism whereby the extended C-terminus of mammalian ALASs allosterically controls the rate of porphyrin biosynthesis might be unraveled.

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Iron, Heme Synthesis and Erythropoietic Porphyrias: A Complex Interplay

Cited by 17 publications

References 66 publications

Microcytosis in Erythropoietic Protoporphyria

Microcytosis in Erythropoietic Protoporphyria

Regulation of Heme Synthesis by Mitochondrial Homeostasis Proteins

An Extended C-Terminus, the Possible Culprit for Differential Regulation of 5-Aminolevulinate Synthase Isoforms

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